rs786204549

Positions:

• chr17-80113315-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.2140delC (p.His714Thrfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP’s specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed. There is a ClinVar entry for this variant (Variation ID: 188904, 2 star review status) with 2 submtters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274107/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 3.95

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2140del	p.His714ThrfsTer50	frameshift_variant	15/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2140del	p.His714ThrfsTer50	frameshift_variant	15/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188904). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 17723315). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His714Thrfs*50) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2020	Variant summary: GAA c.2140delC (p.His714ThrfsX50) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 223082 control chromosomes. c.2140delC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, McCready_2007, Nallamilli_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Feb 14, 2020	This variant, c.2140delC (p.His714Thrfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP's specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed. There is a ClinVar entry for this variant (Variation ID: 188904, 2 star review status) with 2 submtters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 12, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204549; hg19: chr17-78087114;